Artikel
MGMT mRNA expression predicts clinical outcome in malignant glioma after radiotherapy and/or chemotherapy independent of MGMT promoter methylation
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Autoren
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Niklas Thon
- Department of Neurosurgery, Ludwig-Maximillians University, Munich, Germany
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Simone Kreth
- Department of Anaesthesiology, Ludwig-Maximillians University, Munich, Germany
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Sabina Eigenbrod
- Center for Neuropathology and Prion Research, Ludwig-Maximillians University, Munich, Germany
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Hans Kretzschmar
- Center for Neuropathology and Prion Research, Ludwig-Maximillians University, Munich, Germany
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Joerg C. Tonn
- Department of Neurosurgery, Ludwig-Maximillians University, Munich, Germany
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Friedrich W. Kreth
- Department of Neurosurgery, Ludwig-Maximillians University, Munich, Germany
| Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: Epigenetic silencing of the gene that encodes for O6-Methylguanine-DNA-methyltransferase (MGMT) has been correlated with favourable clinical outcome in patients with malignant gliomas after radio-/chemotherapy using alkylating agents such as temozolomide; It has been hypothesized that MGMT promoter methylation leads to a decreased MGMT mRNA transcriptional activity and subsequent protein expression with a diminished ability of the tumor to repair chemotherapy-induced lesions. The real clinical impact of this assumption, however, still remains controversial. In the current prospective study, we analyzed the predictive impact of MGMT mRNA expression in malignant glioma (64 patients) after radiotherapy and/or chemotherapy with temozolomide and its correlation with the MGMT promoter methylation status.
Methods: Only vital tumor samples harvested from open tumor resections (25 patients) and stereotactic biopsies (39 patients) were used for subsequent analyses. MGMT promoter methylation was determined by methylation-specific PCR (MSP). MGMT mRNA expression was analysed by real-time qPCR and normalized against adequate housekeeping genes. Primary end point was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment response (TR).
Results: Histopathological diagnosis revealed 54 glioblastoma multiforme and 10 anaplastic astrocytomas. Thirty-two tumors were methylated and 32 tumors exhibited a low MGMT transcriptional activity (cut off value: 0.45), respectively. Low MGMT mRNA expression turned out to be a strong predictive factor for PFS, OS and favourable TR in univariate and multivariale models (p<0.0001); Even though the degree of MGMT mRNA expression strongly correlated with the methylation status (p<0.0001), discordant findings were seen in 30% of the patients: Patients with a methylated tumor and high MGMT mRNA expression (15%) did significantly worse than those with low transcriptional activity (p<0.01). Conversely, unmethylated tumors with low MGMT mRNA expression (15% of the unmethylated tumors) did better than their counterparts.
Conclusions: Determination of MGMT mRNA expression is a powerful method for predictive evaluation of malignant glioma patients undergoing chemotherapy with alkylating agents. A substantial rate of discordant findings elucidates the fact that treatment decision in favour of chemotherapy with alkylating agents should not be based on the MGMT methylation status alone.
